Lymph node macrophages bind influenza virus in an MBL-dependent manner but they are not required for humoral immunity to influenza

2010 ◽  
Vol 47 (13) ◽  
pp. 2229-2229
Author(s):  
Santiago F. Gonzalez ◽  
Søren E. Degn ◽  
Michael P. Kuligowski ◽  
Lisa A. Pitcher ◽  
Mary Cloninger ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Lymph Node ◽  
Humoral Immunity ◽  
Dependent Manner

VCAM-1 is a CS1 peptide-inhibitable adhesion molecule expressed by lymph node high endothelium

1993 ◽  
Vol 106 (1) ◽  
pp. 109-119 ◽  
Author(s):  
M.J. May ◽  
G. Entwistle ◽  
M.J. Humphries ◽  
A. Ager
Keyword(s):  
Lymph Node ◽  
Cell Interaction ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Ifn Gamma ◽  
Lymphocyte Adhesion ◽  
Peripheral Lymph ◽  
Endothelial Surface ◽  
Dose Dependent

Previous studies have shown that unactivated lymphocytes bind to CS1 peptide and that the adhesion of these cells to high endothelium is inhibited by CS1 peptide. These results suggest that lymphocyte binding occurs via recognition of the CS1-containing splice variant of fibronectin expressed on the high endothelial surface. We have now extended these studies by determining the role of the CS1 receptor, alpha 4 beta 1 (VLA-4) and the alternative VLA-4 ligand, VCAM-1 in a rat model of lymphocyte-high endothelial cell interaction. Anti-VLA-4 antibody, HP2/1, blocked lymphocyte adhesion to resting and IFN-gamma (interferon-gamma) pretreated cultured high endothelial cells (HEC) in a dose-dependent manner with maximal inhibition of 60%. HP2/1 completely blocked the adhesion of rat lymphocytes to immobilized CS1 peptide and to a recombinant soluble (rs) form of human VCAM-1. Lymphocyte binding to rsVCAM-1 was also completely blocked by CS1 peptide. Anti-rat VCAM-1 monoclonal antibody 5F10 inhibited adhesion to untreated and IFN-gamma-treated HEC equally and its effect at 50% inhibition was slightly less than that of HP2/1. These findings suggest that a CS1 peptide-inhibitable ligand expressed by high endothelium is VCAM-1. The majority of cultured HEC expressed significant levels of VCAM-1 under basal conditions, as did HEV in peripheral lymph nodes. VCAM-1 expression by HEC was upregulated by cytokine pretreatment and the effects were ordered: IFN-gamma > TNF-alpha > IL-1 beta. The results described here demonstrate that rat peripheral lymph node HEC express VCAM-1, its expression is upregulated by cytokines, in particular IFN-gamma, and it supports the adhesion of unactivated lymphocytes. They also suggest that the VLA-4/VCAM-1 adhesion pathway may operate during the constitutive migration of lymphocytes into lymphoid organs. Although the mechanism of CS1 peptide inhibition was not determined, these results show that VCAM-1 is a CS1 peptide-inhibitable ligand and therefore CS1, on its own, cannot be used as a specific indicator of fibronectin activity.

Broadly-neutralizing antibodies that bind to the influenza hemagglutinin stalk domain enhance the effectiveness of neuraminidase inhibitors via Fc-mediated effector functions

2021 ◽  
Author(s):  
Ali Zhang ◽  
Hanu Chaudhari ◽  
Yonathan Agung ◽  
Michael D'Agostino ◽  
Jann Ang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Influenza Virus Infection ◽  
Dependent Manner ◽  
Neuraminidase Inhibitors ◽  
Immune Effector ◽  
Effector Cells ◽  
Individual Level ◽  
Influenza Hemagglutinin ◽  
Stalk Domain

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next generation universal influenza vaccines. Protection provided by hemagglutinin stalk binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level, and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual's titers of stalk-binding antibodies, and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

scholarly journals Massive upregulation of the Fas ligand in lpr and gld mice: implications for Fas regulation and the graft-versus-host disease-like wasting syndrome.

1995 ◽  
Vol 181 (1) ◽  
pp. 393-398 ◽  
Author(s):  
J L Chu ◽  
P Ramos ◽  
A Rosendorff ◽  
J Nikolić-Zugić ◽  
E Lacy ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Fas Ligand ◽  
Target Cells ◽  
Dependent Manner ◽  
Wasting Syndrome ◽  
Positive Target ◽  
Abnormal Cells ◽  
Lymph Node Cells ◽  
Fasl Mrna

Fas-deficient lpr and gld mice develop lymphadenopathy due to the accumulation of T cells with an unusual double negative (DN) (CD4-CD8-) phenotype. Previous studies have shown that these abnormal cells are capable of inducing redirected lysis of certain Fc receptor-positive target cells. Since the Fas ligand (FasL) has recently been shown to be partly responsible for T cell-mediated cytotoxicity, lymph node cells from lpr and gld mice were examined for the expression of FasL mRNA. Northern blot analysis revealed that lymph node cells obtained from lpr and gld mice had a striking increase in the level of expression of FasL mRNA predominantly due to expression in the DN T cells. Furthermore, lpr, but not gld lymph node cells killed the B cell line, A20, in a Fas-dependent manner. These findings indicate that Fas mutations result in a massive up-regulation of FasL which, most likely, results from repetitive exposure to (self) antigen. This phenomenon could explain the lpr-induced wasting syndrome observed when lpr bone marrow-derived cells are adoptively transferred to wild-type recipients.

scholarly journals Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells

2000 ◽  
Vol 74 (17) ◽  
pp. 7738-7744 ◽  
Author(s):  
Sangkon Oh ◽  
Maryna C. Eichelberger
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Ifn Γ ◽  
High Doses ◽  
Type Response

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

IL-33-ILC2 axis represents a potential adjuvant target to increase the cross-protective efficacy of influenza vaccine

2021 ◽  
Author(s):  
Clare M. Williams ◽  
Sreeja Roy ◽  
Danielle Califano ◽  
Andrew N. J. McKenzie ◽  
Dennis W. Metzger ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Humoral Immunity ◽  
Vaccine Efficacy ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Wide Range ◽  
The Cross

Interleukin (IL)-33 is a multifunctional cytokine that mediates type 2 dominated immune responses. In contrast, the role of IL-33 during viral vaccination, which often aims to induce type 1 immunity, has not been fully investigated. Here we examined the effects of IL-33 on influenza vaccine responses. We found that intranasal co-administration of IL-33 with an inactivated influenza virus vaccine increases the vaccine efficacy against influenza infection, not only with the homologous strain, but also heterologous strains including the 2009 H1N1 influenza pandemic strain. The cross-protection was dependent on group 2 innate lymphoid cells (ILC2s), as the beneficial effect of IL-33 on vaccine efficacy was abrogated in ILC2-deficient C57BL/6 Il7r P Cre/+ P Rora P fl/fl P mice. Further, mechanistic studies revealed that IL-33 activated ILC2s potentiate vaccine efficacy by enhancing mucosal humoral immunity, particularly IgA responses, potentially via a Th2 cytokine dependent manner. Our results demonstrate that IL-33-mediated activation of ILC2s is a critical early event that is important for the induction of mucosal humoral immunity, which in turn is responsible for cross-strain protection against influenza. Thus, we reveal a previously unrecognized role for the IL-33/ILC2 axis in establishing broadly protective and long-lasting humoral mucosal immunity against influenza – knowledge that may help develop a universal influenza vaccine. Importance Current influenza vaccines, although capable of protecting against predicted viruses/strains included in the vaccine, are inept at providing cross-protection against emerging/novel strains. Thus, we are in critical need for a universal vaccine that can protect against a wide range of influenza viruses. Our novel findings show that a mucosal vaccination strategy involving the activation of lung ILC2s is highly effective in eliciting cross-protective humoral immunity in the lungs. This suggests that the biology of lung ILC2s can be exploited to increase the cross-reactivity of commercially available influenza subunit vaccines.

scholarly journals Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity

2002 ◽  
Vol 11 (8) ◽  
pp. 787-797 ◽  
Author(s):  
Ryo Suzuki ◽  
Yasuo Yoshioka ◽  
Etsuko Kitano ◽  
Tatsunobu Yoshioka ◽  
Hiroaki Oka ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Complement Components ◽  
Alternative Pathways ◽  
Low Cytotoxicity ◽  
The Complement System

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed “cytomedicine, ” which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic β-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

IFN-γ Treatment at Early Stages of Influenza Virus Infection Protects Mice from Death in a NK Cell-Dependent Manner

2010 ◽  
Vol 30 (6) ◽  
pp. 439-449 ◽  
Author(s):  
Ido D. Weiss ◽  
Ori Wald ◽  
Hanna Wald ◽  
Katia Beider ◽  
Michal Abraham ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Nk Cell ◽  
Influenza Virus Infection ◽  
Dependent Manner ◽  
Early Stages ◽  
Ifn Γ

scholarly journals Vaccination with Vesicular Stomatitis Virus-Vectored Chimeric Hemagglutinins Protects Mice against Divergent Influenza Virus Challenge Strains

2015 ◽  
Vol 90 (5) ◽  
pp. 2544-2550 ◽  
Author(s):  
Alex B. Ryder ◽  
Raffael Nachbagauer ◽  
Linda Buonocore ◽  
Peter Palese ◽  
Florian Krammer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Vesicular Stomatitis Virus ◽  
Humoral Immunity ◽  
Influenza Viruses ◽  
Full Length ◽  
Influenza Vaccines ◽  
Serum Antibodies ◽  
Virus Challenge ◽  
Vaccination Strategies ◽  
Vesicular Stomatitis

ABSTRACTSeasonal influenza virus infections continue to cause significant disease each year, and there is a constant threat of the emergence of reassortant influenza strains causing a new pandemic. Available influenza vaccines are variably effective each season, are of limited scope at protecting against viruses that have undergone significant antigenic drift, and offer low protection against newly emergent pandemic strains. “Universal” influenza vaccine strategies that focus on the development of humoral immunity directed against the stalk domains of the viral hemagglutinin (HA) show promise for protecting against diverse influenza viruses. Here, we describe such a strategy that utilizes vesicular stomatitis virus (VSV) as a vector for chimeric hemagglutinin (cHA) antigens. This vaccination strategy is effective at generating HA stalk-specific, broadly cross-reactive serum antibodies by both intramuscular and intranasal routes of vaccination. We show that prime-boost vaccination strategies provide protection against both lethal homologous and heterosubtypic influenza challenge and that protection is significantly improved with intranasal vaccine administration. Additionally, we show that vaccination with VSV-cHAs generates greater stalk-specific and cross-reactive serum antibodies than does vaccination with VSV-vectored full-length HAs, confirming that cHA-based vaccination strategies are superior at generating stalk-specific humoral immunity. VSV-vectored influenza vaccines that express chimeric hemagglutinin antigens offer a novel means for protecting against widely diverging influenza viruses.IMPORTANCEUniversal influenza vaccination strategies should be capable of protecting against a wide array of influenza viruses, and we have developed such an approach utilizing a single viral vector system. The potent antibody responses that these vaccines generate are shown to protect mice against lethal influenza challenges with highly divergent viruses. Notably, intranasal vaccination offers significantly better protection than intramuscular vaccination in a lethal virus challenge model. The results described in this study offer insights into the mechanisms by which chimeric hemagglutinin (HA)-based vaccines confer immunity, namely, that the invariant stalk of cHA antigens is superior to full-length HA antigens at inducing cross-reactive humoral immune responses and that VSV-cHA vaccine-induced protection varies by site of inoculation, and contribute to the further development of universal influenza virus vaccines.

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